Abstract 6776: Biological characterization of small molecule eIF4E inhibitors to assess their therapeutic potential in cancer

Abstract The dysregulation of translation is a hallmark of cancer that enables rapid changes in the cell proteome to shape oncogenic phenotypes that promote tumor survival. The predominant signaling pathways leading to dysregulation of translational control in cancer are the PI3K-AKT-mTORC1, RAS-RAF-MAPK, and MYC pathways, which all converge on eukaryotic translation initiation factor 4E (eIF4E), an RNA-binding protein which binds to the m7GpppX cap structure at the 5' end of mRNAs to initiate cap-dependent translation. eIF4E is the rate-limiting factor of translation initiation, and its overexpression is known to drive oncogenic transformation, progression, and chemoresistance across many cancers, establishing it as an attractive therapeutic target. Traditionally, target transcripts of eIF4E have been characterized as mRNAs with long 5'-UTR motifs, but recent studies point to context-dependent translation of eIF4E-sensitive transcripts that is contingent on the regulation status of eIF4E. Therefore, we hypothesize that mechanistically distinct eIF4E inhibitors will elicit different phenotypic responses in tumors based on the dysregulation of select pools of eIF4E-sensitive transcripts. Research in our laboratory focuses on developing mechanistically distinct eIF4E inhibitors, including m7GpppX prodrug derivatives which bind directly to the cap-binding pocket of eIF4E. Efforts to characterize the effects of these molecules on cap-dependent translation regulation through cell-based phenotypic assays and ribosome profiling will be discussed. Citation Format: Rachel L. O'Rourke, Emilio L. Cárdenas, Jesse Duque, Amanda Falzetta, Jim Clauwaert, Jason Rech, John R. Prensner, Amanda L. Garner. Biological characterization of small molecule eIF4E inhibitors to assess their therapeutic potential in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6776.